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The effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity and cardiovascular biomarkers in patients with stable coronary heart disease or coronary heart disease risk equivalent: the results of a multicenter, randomized, double-blind, placebo-controlled study.
J Am Coll Cardiol. 2008 Apr 29; 51(17):1632-41.JACC

Abstract

OBJECTIVES

This study examined the effects of darapladib, a selective lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) inhibitor, on biomarkers of cardiovascular (CV) risk.

BACKGROUND

Elevated Lp-PLA(2) levels are associated with an increased risk of CV events.

METHODS

Coronary heart disease (CHD) and CHD-risk equivalent patients (n = 959) receiving atorvastatin (20 or 80 mg) were randomized to oral darapladib 40 mg, 80 mg, 160 mg, or placebo once daily for 12 weeks. Blood samples were analyzed for Lp-PLA(2) activity and other biomarkers.

RESULTS

Baseline low-density lipoprotein cholesterol (LDL-C) was 67 +/- 22 mg/dl. Plasma Lp-PLA(2) was higher in older patients (>or=75 years), in men, in those taking atorvastatin 20 mg, at LDL-C >or=70 mg/dl or high-density lipoprotein cholesterol (HDL-C) <40 mg/dl, or in those with documented vascular disease (multivariate regression; p < 0.01). Darapladib 40, 80, and 160 mg inhibited Lp-PLA(2) activity by approximately 43%, 55%, and 66% compared with placebo (p < 0.001 weeks 4 and 12). Sustained dose-dependent inhibition was noted overall in both atorvastatin groups and at different baseline LDL-C (>or=70 vs. <70 mg/dl) and HDL-C (<40 vs. >or=40 mg/dl). At 12 weeks, darapladib 160 mg decreased interleukin (IL)-6 by 12.3% (95% confidence interval [CI] -22% to -1%; p = 0.028) and high-sensitivity C-reactive protein (hs-CRP) by 13.0% (95% CI -28% to +5%; p = 0.15) compared with placebo. The Lp-PLA(2) inhibition produced no detrimental effects on platelet biomarkers (P-selectin, CD40 ligand, urinary 11-dehydrothromboxane B(2)). No major safety concerns were noted.

CONCLUSIONS

Darapladib produced sustained inhibition of plasma Lp-PLA(2) activity in patients receiving intensive atorvastatin therapy. Changes in IL-6 and hs-CRP after 12 weeks of darapladib 160 mg suggest a possible reduction in inflammatory burden. Further studies will determine whether Lp-PLA(2) inhibition is associated with favorable effects on CV events.

Authors+Show Affiliations

University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. mohlere@uphs.upenn.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article
Multicenter Study
Randomized Controlled Trial

Language

eng

PubMed ID

18436114

Citation

Mohler, Emile R., et al. "The Effect of Darapladib On Plasma Lipoprotein-associated Phospholipase A2 Activity and Cardiovascular Biomarkers in Patients With Stable Coronary Heart Disease or Coronary Heart Disease Risk Equivalent: the Results of a Multicenter, Randomized, Double-blind, Placebo-controlled Study." Journal of the American College of Cardiology, vol. 51, no. 17, 2008, pp. 1632-41.
Mohler ER, Ballantyne CM, Davidson MH, et al. The effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity and cardiovascular biomarkers in patients with stable coronary heart disease or coronary heart disease risk equivalent: the results of a multicenter, randomized, double-blind, placebo-controlled study. J Am Coll Cardiol. 2008;51(17):1632-41.
Mohler, E. R., Ballantyne, C. M., Davidson, M. H., Hanefeld, M., Ruilope, L. M., Johnson, J. L., & Zalewski, A. (2008). The effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity and cardiovascular biomarkers in patients with stable coronary heart disease or coronary heart disease risk equivalent: the results of a multicenter, randomized, double-blind, placebo-controlled study. Journal of the American College of Cardiology, 51(17), 1632-41. https://doi.org/10.1016/j.jacc.2007.11.079
Mohler ER, et al. The Effect of Darapladib On Plasma Lipoprotein-associated Phospholipase A2 Activity and Cardiovascular Biomarkers in Patients With Stable Coronary Heart Disease or Coronary Heart Disease Risk Equivalent: the Results of a Multicenter, Randomized, Double-blind, Placebo-controlled Study. J Am Coll Cardiol. 2008 Apr 29;51(17):1632-41. PubMed PMID: 18436114.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity and cardiovascular biomarkers in patients with stable coronary heart disease or coronary heart disease risk equivalent: the results of a multicenter, randomized, double-blind, placebo-controlled study. AU - Mohler,Emile R,3rd AU - Ballantyne,Christie M, AU - Davidson,Michael H, AU - Hanefeld,Markolf, AU - Ruilope,Luis M, AU - Johnson,Joel L, AU - Zalewski,Andrew, AU - ,, PY - 2007/09/26/received PY - 2007/11/07/revised PY - 2007/11/21/accepted PY - 2008/4/26/pubmed PY - 2008/6/5/medline PY - 2008/4/26/entrez SP - 1632 EP - 41 JF - Journal of the American College of Cardiology JO - J. Am. Coll. Cardiol. VL - 51 IS - 17 N2 - OBJECTIVES: This study examined the effects of darapladib, a selective lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) inhibitor, on biomarkers of cardiovascular (CV) risk. BACKGROUND: Elevated Lp-PLA(2) levels are associated with an increased risk of CV events. METHODS: Coronary heart disease (CHD) and CHD-risk equivalent patients (n = 959) receiving atorvastatin (20 or 80 mg) were randomized to oral darapladib 40 mg, 80 mg, 160 mg, or placebo once daily for 12 weeks. Blood samples were analyzed for Lp-PLA(2) activity and other biomarkers. RESULTS: Baseline low-density lipoprotein cholesterol (LDL-C) was 67 +/- 22 mg/dl. Plasma Lp-PLA(2) was higher in older patients (>or=75 years), in men, in those taking atorvastatin 20 mg, at LDL-C >or=70 mg/dl or high-density lipoprotein cholesterol (HDL-C) <40 mg/dl, or in those with documented vascular disease (multivariate regression; p < 0.01). Darapladib 40, 80, and 160 mg inhibited Lp-PLA(2) activity by approximately 43%, 55%, and 66% compared with placebo (p < 0.001 weeks 4 and 12). Sustained dose-dependent inhibition was noted overall in both atorvastatin groups and at different baseline LDL-C (>or=70 vs. <70 mg/dl) and HDL-C (<40 vs. >or=40 mg/dl). At 12 weeks, darapladib 160 mg decreased interleukin (IL)-6 by 12.3% (95% confidence interval [CI] -22% to -1%; p = 0.028) and high-sensitivity C-reactive protein (hs-CRP) by 13.0% (95% CI -28% to +5%; p = 0.15) compared with placebo. The Lp-PLA(2) inhibition produced no detrimental effects on platelet biomarkers (P-selectin, CD40 ligand, urinary 11-dehydrothromboxane B(2)). No major safety concerns were noted. CONCLUSIONS: Darapladib produced sustained inhibition of plasma Lp-PLA(2) activity in patients receiving intensive atorvastatin therapy. Changes in IL-6 and hs-CRP after 12 weeks of darapladib 160 mg suggest a possible reduction in inflammatory burden. Further studies will determine whether Lp-PLA(2) inhibition is associated with favorable effects on CV events. SN - 1558-3597 UR - https://www.unboundmedicine.com/medline/citation/18436114/The_effect_of_darapladib_on_plasma_lipoprotein_associated_phospholipase_A2_activity_and_cardiovascular_biomarkers_in_patients_with_stable_coronary_heart_disease_or_coronary_heart_disease_risk_equivalent:_the_results_of_a_multicenter_randomized_double_blind_placebo_controlled_study_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0735-1097(08)00569-X DB - PRIME DP - Unbound Medicine ER -